Heart transplantation is a life-saving procedure for patients with incurable chronic cardiac diseases. However, immunological rejection remains the main obstacle to long-term survival of cardiac transplants. Three years after transplantation, nearly 30% of the cardiac grafts are rejected. Despite recent advances in immunosuppressive therapy, such treatment is often non-specific and often associated with increased risks of infection and cancer in transplanted patients. In addition, it is generally poorly effective in preventing chronic rejection. Consequently, it is crucial to design selective antigen-specific therapies to achieve long lasting immune tolerance to donor organs; a task that requires elucidation of the cellular and molecular mechanisms underlying the allograft rejection process.
Acute rejection is generally regarded as rejection occurring within the first six months of transplantation. Acute rejection can be diagnosed relatively easily, for example, in the case of a cardiac transplant by the appearance of certain cell types in biopsy cell infiltrate. Chronic rejection, generally regarded as that occurring at least six months after transplantation, is very difficult to diagnose clinically, and may not manifest itself clearly for some years, by which time treatment is generally unsuccessful.
In chronic rejection there is typically found to be vasculopathy in the rejected organ, and the coronary artery disease known as xe2x80x9cacceleratedxe2x80x9d or xe2x80x9ctransplant-associatedxe2x80x9d coronary artery disease. A number of risk factors, e.g. numbers of acute rejection episodes, type of immunosuppression, serum lipid levels, viral infections, etc., contribute to the development of this serious chronic complication following cardiac transplantation. Strategies for blocking T-cell costimulation may help prevent chronic rejection in clinical transplantation.
The contractile proteins found in cardiac muscle, which include myosin heavy and light chains, have particular significance for cardiac performance. The expression of these proteins correlates with development of the tissues. The initial formation of skeletal muscle fibers is accompanied by the expression of muscle-type actin and myosin genes. Genes expressed in adult cardiac tissue are coexpressed with the corresponding skeletal muscle sequence during fetal development. During subsequent maturation of muscle fibers in vivo, developmental changes in the expression of fetal/adult isoforms of these proteins occur, shifting to the cardiac forms.
Two types of myosin heavy chain (MYHC) are expressed in the mammalian heart, xcex1- and xcex2-MYHC; and the contractile velocity of the heart is correlated with the relative amount of each MYHC. The xcex1-MYHC has a high ATPase activity than xcex2-MYHC, and while hearts expressing more xcex1-MYHC have a more rapid contractile velocity, hearts with more xcex2-MYHC allow for greater economy in force generation. The MYHC composition of the ventricular myocardium of humans has been reported to be greater than 95% xcex2-MYHC. The xcex1-MYHC gene is expressed also in a trial muscle and the xcex2-MYHC gene in skeletal slow-twitch muscle.
During graft rejection, there is tissue damage and cell death, which results in the cellular proteins being released into the bloodstream, including contractile proteins. The use of antimyosin antibodies has therefore been applied to determine whether there is ongoing myocarditis, myocardial infarction, or cardiac rejection in a patient (see Schutz et al. (1997) Ann Thorac Surg 63(2):578-81 for a review). Antimyosin scintigraphy after the application of indium 111-labeled antimyosin antibodies is a useful tool to detect or exclude noninvasively cardiac rejection in adults and children.
The current methods of heart transplantation result in rejection of a significant proportion of the grafts. Methods of preventing and diagnosing rejection are of great clinical interest.
Relevant Literature
The role indirect allorecognition during transplant rejection is reviewed by Benichou et al. (1997) Immunol Today 18(2):67-71. Although the initial indirect alloresponse is limited to a few dominant determing on donor major histocompatibility complex (MHC) molecules, subsequent spreading to additional determinants on recipient and donor antigens is common. Fedoseyeva et al. (1996) Transplantation 61(5):679-683 show that the breakdown of tolerance to an MHC self-peptide resulted from the presentation of the donor crossreactive peptide at the surface of recipient antigen-presenting cells.
Methods are provided for the improved diagnosis and prevention of allograft rejection associated with heart transplantation. A loss of tolerance to autologous contractile proteins expressed in cardiac cells, e.g. cardiac myosin heavy chain alpha, is shown to be a factor in the development of cellular immunity against an engrafted allogeneic heart. The detection of host T cells that are immunoreactive with such autologous proteins is useful as a diagnostic for development of chronic rejection in a heart recipient. Methods are also provided for tolerizing the host and for maintaining existing tolerance of cardiac proteins, in order to improve the long term survival of heart transplants.